Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated acute sensitization by nerve growth factor (NGF) of the response of small-diameter (<30 microm) dissociated dorsal root ganglion (DRG) cells to brief repeated puffs of capsaicin as a model for thermal hyperalgesia induced by NGF. We have previously shown that placing NGF in the bath after an initial puff of capsaicin can completely overcome the tachyphylaxis normally observed in response to a second puff 10 min later, and this response is often substantially larger than the first. If tachyphylaxis is abolished by carrying out the experiment in Ca2+-free solution, NGF still elicits potentiation of the second puff. However, the amount of potentiation is considerably less than that observed when tachyphylaxis also takes place. Thus it is concluded that NGF has two effects: overcoming tachyphylaxis and potentiation. With three puffs of capsaicin separated by 10 min, we have found that the potentiation established after 10 min exposure to NGF is no longer evident 10 min after removal of NGF. In Ca2+-free solution the potentiation can last up to 1 h after removal of NGF. These results suggest that the initial behavioral sensitization elicited by NGF could result from a direct effect on the sensory neuron but that its later components most likely involve other mechanisms. We have also investigated the contribution of various second-messenger pathways in these actions of NGF by treating the cells with blockers of MAP kinase (PD98059), protein kinase A (PKA; PKAI14-22, H89), and PKC (Bisindolylmaleimide I). Surprisingly, PD98059, which previously has been shown to diminish the enhancement of capsaicin responses of dissociated neurons when exposed to NGF for several days, had no effect on the acute response to NGF; nor did the PKC inhibitor. However, PKA inhibitors reduced the capsaicin response of the cells to NGF (as determined from the NGF effect on tachyphylaxis). Consistent with these findings we confirmed that forskolin, a PKA activator, enhances the effect of NGF on the capsaicin response. The percentage of small cells sensitized by NGF under these conditions, as determined by its ability to reduce tachyphylaxis, was 64%. This suggests that about two-thirds of DRG cells <30 microm and sensitive to capsaicin express a functional trkA receptor.
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PMID:Acute sensitization by NGF of the response of small-diameter sensory neurons to capsaicin. 1173 49

The effect of parathyroid hormone (PTH) and activation of protein kinase C (PKC) and protein kinase A (PKA) on transepithelial P(i) transport was examined in monolayers of chick proximal tubule cells in primary culture (PTCs). Acute exposure of the PTCs to PTH (10(-9) M, basolateral side) significantly decreased the net reabsorption of P(i) by approximately 66%. There was no effect after the addition of PTH to the luminal side. Activation of PKC by phorbol 12-myristate 13-acetate (PMA; 0.1 microM) dramatically decreased net P(i) reabsorption by approximately 60%. Bisindolylmaleimide I (BIM; 1 microM), a highly selective PKC inhibitor, prevented PMA-induced inhibition. Activation of adenylate cyclase/PKA by forskolin (10 microM) mimicked the effect of PTH by significantly reducing net P(i) reabsorption by one-half. Addition of H-89 (10 microM), a potent inhibitor of PKA, abolished forskolin-induced inhibition. PTH inhibition was blocked by either BIM or H-89. Tissue electrophysiology remained stable after all treatments. There was a decreased immunoreactivity of the luminal Na+-P(i) cotransporter NaPi-IIa after PTH treatment. These data indicate that PTH inhibition of P(i) reabsorption in this in vitro system is mediated by PKC and PKA.
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PMID:Regulation of transepithelial phosphate transport by PTH in chicken proximal tubule epithelium. 1174 32

Thromboxane A(2) (TXA(2)) stimulates mitogenic growth of vascular smooth muscle. In humans, TXA(2) signals through two TXA(2) receptor (TP) isoforms, termed TPalpha and TPbeta. To investigate the mechanism of TXA(2)-mediated mitogenesis, regulation of extracellular signal-regulated kinase (ERK) signaling was examined in human embryonic kidney 293 cells stably overexpressing the individual TP isoforms. The TXA(2) mimetic 9,11-dideoxy-9alpha,11alpha-methano epoxy prostaglandin F(2alpha) (U46619) elicited concentration- and time-dependent activation of ERK1 and -2 through both TPs with maximal TPalpha- and TPbeta-mediated ERK activation observed after 10 and 5 min, respectively. U46619-mediated ERK activation was inhibited by the TP antagonist [1S-[1alpha,2beta-(5Z)-3beta,4alpha-]]-7-[3-[[2-(phenylamino)carbonyl]hydrazine] methyl]-7-oxabicyclo[-2,2,1-]hept-2yl]-5-heptenoic acid (SQ29,548), and by the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD 98059). Although ERK activation through TPalpha was dependent on 2-[1-(dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF 109203X)-sensitive protein kinase (PK) Cs, ERK activation through TPbeta was only partially dependent on PKCs. ERK activation through both TPalpha and TPbeta was dependent on PKA and phosphoinositide 3-kinase (PI3K) class 1(A), but not class 1(B), and was modulated by Harvey-Ras, A-Raf, c-Raf, and Rap1B/B-Raf and also involved transactivation of the epidermal growth factor receptor. Additionally, PKB/Akt was activated through TPalpha and TPbeta in a PI3K-dependent manner. In conclusion, we have defined the key components of TXA(2)-mediated ERK signaling and have established that both TPalpha and TPbeta are involved. TXA(2)-mediated ERK activation through the TPs is a complex event involving PKC-, PKA-, and PI3K-dependent mechanisms in addition to transactivation of the EGF receptor. TPalpha and TPbeta mediate ERK activation through similar mechanisms, although the time frame for maximal ERK activation and PKC dependence differs.
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PMID:Regulation of extracellular signal-regulated kinase cascades by alpha- and beta-isoforms of the human thromboxane A(2) receptor. 1190 Dec 21

We recently identified a novel mechanism explaining how the mouse (m) prostacyclin receptor (IP) couples to Galpha(s), Galpha(i), and Galpha(q) (Lawler, O. A., Miggin, S. M., and Kinsella, B. T. (2001) J. Biol. Chem. 276, 33596-33607) whereby mIP coupling to Galpha(i) and Galpha(q) is dependent on its initial coupling to Galpha(s) and subsequent phosphorylation by cAMP-dependent protein kinase A (PKA) on Ser(357). In the current study, the generality of that mechanism was investigated by examining the G protein coupling specificity of the human (h) IP. The hIP efficiently coupled to Galpha(s)/adenylyl cyclase and to Galpha(q)/phospholipase C activation but failed to couple to Galpha(i). Coupling of the hIP to Galpha(q), or indeed to Galpha(s) or Galpha(i), was unaffected by the PKA or protein kinase C (PKC) inhibitors H-89 and GF 109203X, respectively. Thus, mIP and hIP exhibit essential differences in their coupling to Galpha(i) and in their dependence on PKA in regulating their coupling to Galpha(q). Analysis of their primary sequences revealed that the critical PKA phosphorylation site within the mIP, at Ser(357), is replaced by a PKC site within the hIP, at Ser(328). Conversion of the PKC site of the hIP to a PKA site generated hIP(QL325,326RP) that efficiently coupled to Galpha(s) and to Galpha(i) and Galpha(q); coupling of hIP(QL325,326RP) to Galpha(i) but not to Galpha(s) or Galpha(q) was inhibited by H-89. Abolition of the PKC site of the hIP generated hIP(S328A) that efficiently coupled to Galpha(s) and Galpha(q) but failed to couple to Galpha(i). Finally, conversion of the PKA site at Ser(357) within the mIP to a PKC site generated mIP(RP354,355QL) that efficiently coupled to Galpha(s) but not to Galpha(i) or Galpha(q). Collectively, our data highlight critical differences in signaling by the mIP and hIP that are regulated by their differential phosphorylation by PKA and PKC together with contextual sequence differences surrounding those sites.
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PMID:Investigation of the mechanisms of G protein: effector coupling by the human and mouse prostacyclin receptors. Identification of critical species-dependent differences. 3007 57

Irreversible cell cycle withdrawal occurs as normal keratinocytes detach from the basement membrane and initiate their terminal differentiation program. To investigate which signaling pathways regulate this permanent cell cycle withdrawal, we added inhibitors of kinases implicated in integrin signaling and keratinocyte differentiation to normal human keratinocytes induced to differentiate in suspension culture, and assayed the growth capacity of the recovered cells. Keratinocytes suspended in methylcellulose for 24 h underwent approximately 1000-fold loss of proliferative capacity. Of the kinase inhibitors tested, only the protein kinase C inhibitor Bisindolylmaleimide I (GF109203X) caused dramatic protection from loss of growth potential. Direct activation of protein kinase C by 12-O-tetradecanoyl-phorbol-13-acetate was also sufficient to trigger irreversible growth arrest. Protein kinase C inhibitors selective for protein kinase Calpha, the only Ca2+-dependent protein kinase C isoform in keratinocytes, protected keratinocytes from suspension-induced cell cycle withdrawal. Consistent with this finding, we measured a specific induction of Ca2+-dependent protein kinase C activity 2-3 h after keratinocytes were placed into suspension culture. Furthermore, protein kinase Calpha was strongly localized to cell membranes in the suprabasal keratinocytes of human epidermis, suggesting translocation and activation in vivo. Coordinated changes in cell cycle regulators (p21, p27, pRb, p107, p130) consistent with cells exiting the cell cycle were observed in suspended keratinocytes, and these changes were blocked by protein kinase C inhibition. These results indicate that the loss of cell matrix adhesion triggers protein kinase C activation, which is an early event required for cell cycle withdrawal of terminally differentiating normal human keratinocytes.
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PMID:Activation of protein kinase C triggers irreversible cell cycle withdrawal in human keratinocytes. 1248 29

Recently we reported that the pyridinylimidazole class of p38 mitogen-activated protein (MAP) kinase inhibitors potently inhibited the facilitated transport of nucleosides and nucleoside analogs in K562 cells. These compounds competed with the binding of nitrobenzylthioinosine (NBMPR) to K562 cells, consistent with inhibition of the NBMPR-sensitive equilibrative transporter (ENT1). In this study we examined a large number of additional protein kinase inhibitors for their effects on nucleoside transport. We find that incubation of K562 cells with tyrosine kinase inhibitors (AG825, AG1517, AG1478, STI-571), protein kinase C (PKC) inhibitors (staurosporine, GF 109203X, R0 31-8220, arcyriarubin A), cyclin-dependent kinase inhibitors (roscovitine, olomoucine, indirubin-3'-monoxime), or rapamycin resulted in a dose-dependent reduction of intracellular uptake of [3H]uridine. In contrast, neither the MAP kinase kinase inhibitors (U0126, PD 98059) nor the phosphatidyl inositol-3 kinase inhibitors (wortmannin, LY 294002) affected this process. Furthermore, both transient uptake and prolonged [3H]thymidine incorporation in K562 cells were inhibited by protein kinase inhibitors, inactive analogs of kinase inhibitors (R0 31-6045, SB202474), and NBMPR, independently of effects on cell proliferation as determined by MTT assay. These studies demonstrate that a wide variety of protein kinase inhibitors affect nucleoside uptake through selective inhibition of nucleoside transporters, independently of kinase inhibition.
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PMID:Inhibition of nucleoside transport by protein kinase inhibitors. 1253 31

In certain cardiovascular disorders, such as congestive heart failure and ischemic heart disease, several endogenous regulators, including norepinephrine (NE) and endothelin-1 (ET-1), are released from various types of cell. Because plasma levels of these regulators are elevated, it seems likely that cardiac contraction might be regulated by crosstalk among these endogenous regulators. We studied the regulation of cardiac contractile function by crosstalk between ET-1 and NE and its relationship to Ca2+ signaling in canine ventricular myocardium. ET-1 alone did not affect the contractile function. However, in the presence of NE at subthreshold concentrations (0.1 to 1 nmol/L), ET-1 had a positive inotropic effect (PIE). In the presence of NE at higher concentrations (100 to 1000 nmol/L), ET-1 had a negative inotropic effect. ET-1 had a biphasic inotropic effect in the presence of NE at an intermediate concentration (10 nmol/L). The PIE of ET-1 was associated with an increase in myofilament sensitivity to Ca2+ ions and a small increase in Ca2+ transients, which required the simultaneous activation of protein kinase A (PKA) and PKC. ET-1 elicited translocation of PKCepsilon from cytosolic to membranous fraction, which was inhibited by the PKC inhibitor GF 109203X. Whereas the Na+-H+ exchange inhibitor Hoe 642 suppressed partially the PIE of ET-1, detectable alteration of pHi did not occur during application of ET-1 and NE. The negative inotropic effect of ET-1 was associated with a pronounced decrease in Ca2+ transients, which was mediated by pertussis toxin-sensitive G proteins, activation of protein kinase G, and phosphatases. When the inhibitory pathway was suppressed, ET-1 had a PIE even in the absence of NE. Our results indicate that the myocardial contractility is regulated either positively or negatively by crosstalk between ET-1 and NE through different signaling pathways whose activation depends on the concentration of NE in the dog.
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PMID:Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothelin-1 and norepinephrine in dog ventricular myocardium. 1269 35

4-aminopyridine (4AP) is a general blocker of voltage-dependent K+ channels. This pyridine derivative has also been shown to inhibit T cell proliferation, to modulate immune responses and to alleviate some of the symptoms associated with neurological disorders such as multiple sclerosis, myasthenia gravis and Alzheimer's disease. 4AP triggers a Ca2+ response in lymphocytes, astrocytes, neurons and muscle cells but little is known about the regulation of the 4AP response in these cells. We report that 4AP induced a non-capacitative transplasma membrane influx of Ca2+ in Jurkat T lymphocytes. The influx of Ca2+ was not affected by activation or inhibition of protein kinase A (PKA). In contrast, activation of protein kinase C (PKC) by phorbol myristyl acetate (PMA), mezerein or 1-oleoyl-2-acetyl-sn-glycerol (OAG) inhibited the influx of Ca2+ triggered by 4AP. The inhibitory effect of PKC could be prevented by prior exposure of the cells to the PKC inhibitor GF 109203X. Under these conditions, mezerein and OAG no longer inhibited the 4AP-dependent Ca2+ response. Inhibition of serine and threonine protein phosphatases PP1 and PP2A by treating the cells with calyculin A (CalA) reduced the Ca2+ response to 4AP. Okadaic acid (OA) had no effect, suggesting an involvement of PP1. A combination of CalA and OAG (or PMA) abolished the influx of Ca2+ induced by 4AP, adding further evidence to the importance of protein phosphorylation in the modulation of the 4AP response. Our data suggest that the transplasma membrane influx of Ca2+ triggered by 4AP in Jurkat T cells can be modulated by the opposite actions of PKC and protein serine and threonine phosphatase(s).
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PMID:Protein kinase C inhibits the transplasma membrane influx of Ca2+ triggered by 4-aminopyridine in Jurkat T lymphocytes. 1288 Sep 46

CKS-17, a synthetic peptide representing a unique amino acid motif which is highly conserved in retroviral transmembrane proteins and other immunoregulatory proteins, induces selective immunomodulatory functions, both in vitro and in vivo, and activates intracellular signaling molecules such as cAMP and extracellular signal-regulated kinases. In the present study, using Jurkat T-cells, we report that CKS-17 phosphorylates protein kinase D (PKD)/protein kinase C (PKC) mu. Total cell extracts from CKS-17-stimulated Jurkat cells were immunoblotted with an anti-phospho-PKCmu antibody. The results show that CKS-17 significantly phosphorylates PKD/PKCmu in a dose- and time-dependent manner. Treatment of cells with the PKC inhibitors GF 109203X and Ro 31-8220, which do not act directly on PKD/PKCmu, attenuates CKS-17-induced phosphorylation of PKD/PKCmu. In contrast, the selective protein kinase A inhibitor H-89 does not reverse the action of CKS-17. Furthermore, a phospholipase C (PLC) selective inhibitor, U-73122, completely blocks the phosphorylation of PKD/PKCmu by CKS-17 while a negative control U-73343 does not. In addition, substitution of lysine for arginine residues in the CKS-17 sequence completely abrogates the ability of CKS-17 to phosphorylate PKD/PKCmu. These results clearly indicate that CKS-17 phosphorylates PKD/PKCmu through a PLC- and PKC-dependent mechanism and that arginine residues play an essential role in this activity of CKS-17, presenting a novel modality of the retroviral peptide CKS-17 and molecular interaction of this compound with target cells.
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PMID:A retroviral-derived peptide phosphorylates protein kinase D/protein kinase Cmu involving phospholipase C and protein kinase C. 1289 47

It has been shown that oxidized low-density lipoprotein (ox-LDL), through the activation of glomerular cells, stimulates pathobiological processes involved in monocyte infiltration into the mesangium. The underlying molecular mechanisms are not fully understood. The present study showed that ox-LDL strongly induced AP-1 binding activity in rat mesangial cells (RMCs) in a dose- and time-dependent manner, reaching the maximal activation at 250 microg ml(-1) within 24 h. The results from mobility shift assays and Western blotting analysis revealed that this AP-1 binding increase involved c-Jun, but not c-Fos. Moreover, this ox-LDL-increased AP-1 binding was inhibited by several protein kinase (PK) inhibitors: the protein kinase C (PKC) inhibitor Bisindolylmaleimide I, the cAMP-dependent PK (PKA) inhibitor H89, and the tyrosine PK (PTK) inhibitor genistein. Protein phosphorylation represents mitogen-activated protein kinase (MAPK) activity. Therefore, we examined the role of ox-LDL on the activation of mesangial cell JNK/SAPK, the only recognized protein kinase that catalyses phosphorylation of c-Jun. The incubation of mesangial cells with ox-LDL induced phosphorylation of JNK1/SAPK dose dependently, with the maximal response at 150 microg ml(-1). This study demonstrates that multiple kinase activities are involved in the mechanism of ox-LDL-induced AP-1 activation in mesangial cells, and ox-LDL stimulates AP-1 through JNK-c-Jun other than MEK-c-Fos signalling pathway.
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PMID:Oxidized LDL induces transcription factor activator protein-1 in rat mesangial cells. 1291 Apr 78


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